Process and intermediates for production of donepezil and related compounds

ABSTRACT

The present invention relates to a new process for the preparation of acetylcholinesterase inhibitors of formula (I) or a salt thereof, wherein: R 1  is N-acyl-4-piperidyl; N-alkoxycarbonyl-4-piperidyl; N-alkyl-4-piperidyl; N-benzyl-4-piperidyl; N-(ω-aralkyl)-4-piperidyl; 4-pyridyl; R 4 , R 5 , R 6 , and R 7  are identical or different and each represents hydrogen, straight-chain or branched alkyl, aryl, hydroxy, alkoxy, aryloxy, benzyloxy, acyloxy, alkylthio, arylthio, benzylthio, acylamino, phthalimido or halogen; n is 1, 2 or 3; m is 1, 2, 3, 4, or 5. This process comprises cyclisation of a compound of formula (II) or salts thereof, wherein R 1 , R 4 , R 5 , R 6  and R 7 , m and n are as defined above; R 2  is selected from a derivatised or non-derivatised carboxyl, cyano, N-substituted aminocarbonyl groups or hydrogen; R 3  is selected from a derivatised or non-derivatised carboxyl, cyano or N-substituted aminocarbonyl groups, optionally in the presence of acids and/or solvents. One of the most potent acetylcholinesterase inhibitors of the class of compounds prepared according to the present invention is donepezil.

REFERENCE TO RELATED APPLICATIONS

The present application is the national stage under 35 U.S.C. 371 ofinternational application PCT/IL99/00436, filed Aug. 11, 1999 whichdesignated the United States, which international application waspublished under PCT Article 21 (2) in English.

FIELD OF THE INVENTION

The present invention relates to a new process for the preparation ofacetylcholinesterase inhibitors (anti-AchE) such as Donepezil, to somenovel intermediates used in this process and to their preparation.

BACKGROUND OF THE INVENTION

Dementia is a chronic progressive organic mental disorder in which thereis disturbance of multiple higher cortical functions including memory,thinking, orientation, comprehension, calculation, learning capacity,language and judgement. Alzheimer's Disease is the commonest cause ofdementia and is characterized by degeneration of specific nerve cells,presence of neurotic plaques, and neurofibrillary tangles. Definitivediagnosis of Alzheimer's Disease requires demonstration of thesecharacteristic pathological features in brain tissue, although in thevast majority of cases diagnosis is made on clinical grounds alone,where it is more correctly called Senile Dementia of the Alzheimer Type(SDAT).

Various attempts have been made to treat the senile dementia with adrug. It was found that compounds of formula [X] (Scheme 1) possess ahigh acetylcholinesterase inhibitory activity (Sugimoto, H., et al., J.Med. Chem., v. 38, 481 (1995). One of the most potentacetylcholinesterase inhibitors (anti-AChE) of this class is Donepezil(E2020) [VII].

Donepezil is a new drug treatment for use in mild to moderate dementiadue to SDAT. Donepezil acts by inhibiting acetylcholine esterase, theenzyme responsible for metabolising acetylcholine, thereby enhancingneurotransmitter levels.

The general synthetic route to compounds [X] comprises the condensationof cyclic aromatic ketones [XI] with1-substituted-4-(ω-formylalkyl)piperidines [XII] followed by reductionof the obtained compounds [XIII] (Scheme 1) (Sugimoto, H., et al., J.Med. Chem., v. 38, 481 (1995); Eisai Co., U.S. Pat. No. 5,100,901).

SUMMARY OF INVENTION

The present invention relates to a process for preparing a compound offormula [I] or a salt thereof:

wherein:

R¹ is N-acyl-4-piperidyl; N-alkoxycarbonyl-4-piperidyl; 4-piperidyl;N-alkyl-4-piperidyl; N-benzyl-4-piperidyl; N-(ω-aralkyl)-4-piperidyl;4-pyridyl;

R⁴, R⁵, R⁶ and R⁷ are identical or different and each representshydrogen, straight-chain or branched alkyl, aryl, hydroxy, alkoxy,aryloxy, benzyloxy, acyloxy, alkylthio, arylthio, benzylthio, acylamino,phthalimido or halogen;

n is 1, 2 or 3;

m is 1, 2, 3, 4 or 5;

which process comprises cyclisation of a compound of formula [II] orsalts thereof

wherein

R¹, R⁴, R⁵, R⁶ and R⁷, m and n are as defined above;

R² is selected from a derivatised or non-derivatised carboxyl, cyano,N-substituted aminocarbonyl groups or hydrogen;

R³ is selected from a derivatised or non-derivatised carboxyl, cyano orN-substituted aminocarbonyl groups, optionally in the presence of acidsand/or solvents.

According to the present invention, enantiomerically enriched compoundsof formula [I] or salts thereof are prepared by cyclisation of opticallypure compounds of formula [II], wherein R² and R³ are different.

The present invention also relates to new compounds of formula [II]:

wherein

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷, m and n are as defined above, includingsalts thereof and the optically active enantiomers thereof, with theproviso that when R¹ is 4-pyridyl, and n=m=1, then at least one of R⁴,R⁵, R⁶ and R⁷ does not represent hydrogen or lower alkyl.

The present invention further relates to a process for preparing acompound [II] by the hydrogenation of a compound of formula [VIII] or[IX] or mixtures thereof

wherein

R¹, R³, R⁴, R⁵, R⁶, R⁷, n and m are as defined above.

Alternatively, a compound of the formula [II] can be prepared byreaction of a compound of formula [V]

with a compound of the formula [VI]

in the presence of a strong base,

wherein in all the above formulae, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, m andn are as defined above.

Alternatively, a compound of the formula [II] can be prepared byreacting of compound of formula [III]

wherein

X is a facile leaving group,

with a compound of the formula [IV]

in the presence of a strong base as it was shown in one example byMiyoshi, Hideto et. al. (J. Biol. Chem., (1998), 273 (28).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula [I] and formula [II] can be prepared asdescribed in the following reaction schemes and discussion. Unlessotherwise indicated, the meanings R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, n and min compounds of the formulae [I], [Ia], [II], [IIa], [III], [IIIa],[IV], [IVa], [V], [V], [VI], [VII], [IX], [XX], [XX], [VIIa], [IXa],[XVIIIa], [XIXa] which are shown or mentioned in the reaction schemesand discussion tat follow, are as defined above.

Scheme 2 below refers to a process for the preparation of a compound offormula [I] or salts thereof by cyclisation of a compound of formula[II] or salts thereof:

When the above process is carried out with an optically pure compound offormula [II], (R² and R³ are different), the obtained product is anenantiomically enriched compound of formula [I] or salts thereof.

According to the present invention ester, amido, cyano or etherprotecting groups can be hydrolyzed under the conditions of thecyclisation reaction either in the starting compound [II] or in thedesired compound [I].

Preferably, the cyclisation is carried out with a previously hydrolysedcompound [II], wherein R² is hydrogen or a carboxyl group and to R³ is acarboxyl group. Compound [II] wherein R² and R³ are carboxyl groups, aredecarboxylated in the course of the intramolecular acylatin.

More preferably, said cyclisation of compound [II] (R²=H, R³=COOH) iscarried out under Friedel-Crafts reaction conditions, optionally withprevious derivatisation of the R³ carboxylic group to a halocarbonylgroup.

Preferably, the cyclisation of the present invention is carried out inthe presence of protic acids or Lewis acids or a mixture thereof.Examples of such acids are trifluoromethanesulfonic acid,methanesulfonic acid, polyphosphoric acid, fluoro- or chlorosulfonicacid, sulfuric acid, hydrogen fluoride, hydrogen chloride, zincchloride, zinc bromide, aluminium chloride, aluminium bromide, titaniumchloride, boron fluoride, phosphorus pentoxide, phosphorus oxychloride,phosphorus pentachloride, phosphorus trichloride, thyonyl chloride andsulfuryl chloride.

The cyclisaton of the present invention can be carried out in thepresence of a solvent. Preferably, the solvent is selected fromdichloromethane, chloroform, dichloroethane, tetrachloroethane,chlorobenzene, dichlorobenzene, nitromethane, nitroethane, nitrobenzene,ether or mixtures thereof.

Pharmaceutically important compounds of formula [Ia] are obtainedaccording to Scheme 3:

Acids of formula [XV] or [XVI], which are obtained by hydrolysis of thecorresponding esters [XIV] and [XVII], undergo cyclisation to yieldDonepezil [VII] in high yield and purity (Scheme 4).

According to another aspect, the present invention relates to newcompounds of formula [II] including the optically active enantiomersthereof (R²≠R³) which are used in the cyclisation shown in Scheme 2above.

Schemes 5 and 6 below refer to processes for preparation of the newcompounds of formula [II].

Referring to Scheme 5 and 6, the compounds of formulae [III], [IV], [V],[VI], [XVIII], [XIX], [XX], [XXI] can be prepared by methods well knownto those of ordinary skill in the art.

In the above formulae (Scheme 5), X represents a facile leaving groupand may be a sulfonate group or a halogen. Preferably, X is selectedfrom chlorine and bromine.

The reactions according to Scheme 5 are usually carried out in thepresence of a strong base, as for example metal alkoxides, metal amides,metal hydrides or mixtures thereof. Most preferably, the strong base isselected from sodium methoxide, sodium ethoxide, potassiumtert-butoxide, sodium hydride, sodium tert-pentoxide, sodiumbis(trimethylsilyl)amide, lithium diisopropylamide or mixtures thereof.

The coupling reaction according to Scheme 6 is usually carried out inthe presence of a base. Preferably, the base is selected from metalcarbonate, metal alkoxides, metal amides or metal hydrides. Morepreferably, the base is selected from potassium carbonate, sodiummethoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride,lithium diisopropylamide or mixture thereof.

The products of the coupling reaction shown in Scheme 6, i.e compounds[VIII] and [IX] can undergo isomerisation under the reaction conditionsto give either an isomeric mixture or the thermodynamically more stableisomer.

The above process can be carried out either without a solvent or in thepresence of an organic solvent or water. The organic solvent ispreferably selected from tetrahydrofuran (THF), 1,2-dimethoxyethane,dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF),N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, dimethylsulphoxide(DMSO), methanol, ethanol, isopropanol, tert-butyl alcohol or mixturesthereof.

The compounds [VIII] and [IIX] in Scheme 6 can be reduced by catalytichydrogenation. Transition metals can be used as catalysts in saidcatalytic hydrogenation. Preferably, Pd, Pt, Rh, Ru or Ni are used.During this process some of the R¹ groups are reduced (e.g. 4-pyridyl—to4-piperidyl. In such a case it is preferred to protect the nitrogen ofthe piperidyl group).

A compound of formula [IIa] (Scheme 3) may be prepared from thecompounds [IIIa] and [IVa], as shown in the following Schemes 7 and 8.

Compounds [XIV] and [XVII] which can be used in the synthesis ofDonepezil (Scheme 4) may be prepared according to either Scheme 9 orScheme 10.

Enantiomerically enriched compounds of formula [I] are obtained fromoptically pure compounds [II] (Scheme 2), which in turn, are obtainedfrom a racemic mixture of [II] (wherein R²≠R³) by either of thefollowing reactions:

Diastereomeric crystallisation with optically pure acids, followed byseveral recrystallisations and recovery of the desired product;

Diastereomeric crystallisation with optically pure amines (if R² orR³=COOH) followed by a number of recrystallisations and recovery of thedesired product;

Resolution on an optically active sorbent;

Enzymatic resolution.

Furthermore, in order to increase the yield of the optically pureproduct [II], the undesired enantiomer may be racemised and reused.

The present invention will be described in more detail with the aid ofthe following non-limiting examples.

EXAMPLE 1

Preparation of Donepezil (VII)

1.1 Preparation of dimethyl (4-piperidylmethyl)malonate [XXIXa]

A solution of dimethyl (4-pyridylmethylene)malonate [XXVIIIa] (925 g) inmethanol (9 L) was hydrogenated in the presence of glacial acetic acid(360 mL) and 10% palladium on activated carbon catalyst (92.5 g) at 60°C. and 200 psi. The catalyst was filtered off and the resulting solutionof the title compound in the form of acetic acid salt was used directlyin the next step.

1.2 Preparation of dimethyl (N-benzyl-4-piperidylmethyl)malonate [XXIIa]

Sodium carbonate (1,550 g) and benzyl chloride (582.3 g) were added tothe solution of the acetic acid salt of dimethyl(4-piperidylmethyl)malonate [XXIXa] from the previous step. The obtainedslurry was stirred for 12 hours at 60-65° C. and evaporated underreduced pressure. Water was added to the residue and the mixture wasextracted with dichloromethane. The organic layer was washed with water,dried over sodium sulfate, passed through short silica gel column andevaporated under reduced pressure. The residue was washed with hexaneand dried under reduced pressure to give dimethyl(N-benzyl-4-piperidylmethyl)malonate [XXIIa]. ¹H NMR (CDCl₃) δ1.10-1.37(m, 3H), 1.50-1.75 (m, 2H), 1.75-2.00 (m, 4H), 2.83 (br. d, 2H, J=12Hz), 3.44 (s, 2H), 3.70 (s, 6H), 7.26 (m, 5H).

1.3 Preparation of dimethyl(3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonate [XIVa]

A solution of dimethyl (N-benzyl-4-piperidylmethyl)malonate [XXIIa](43.5 g) in THF (100 mL) obtained in the previous step, was addeddropwise to a mixture of sodium hydride, 60% suspension in mineral oil(7.0 g) and THF (60 mL). After the evolution of hydrogen stopped, asolution of 3,4-dimethoxybenzyl chloride [IIIb] (30.7 g) in THF (100 mL)was added dropwise to the mixture. The resulting mixture was refluxedfor 3 hours and then cooled to room temperature. A solution of absoluteethanol (5 mL) in 20 mL THF was carefully added to the mixture until theevolution of hydrogen has stopped. Then the reaction mixture wasconcentrated under reduced pressure to about half volume and treatedwith a mixture of ice and 5% aqueous citric acid followed by theneutralisation with 5% aqueous sodium hydrogen carbonate solution. Theproduct was extracted with dichloromethane, the organic layer was washedwith water, dried over sodium sulfate, passed through a short silica gelcolumn and evaporated to dryness to obtain dimethyl(3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonate [XIVa], ¹H NMR(CDCl₃) δ1.12-1.39 (m, 2H), 1.39-1.60 (m, 3H), 1.77 (d, 2H, J=4 Hz),1.82-2.02 (m, 2H), 2.80 (br. d, 2H, J=11.3 Hz), 3.18 (s, 2H), 3.43 (s,2H), 3.63 (s, 6H), 3.77 (s, 3H), 3.79 (s, 3H), 6.51-6.63 (m, 2H),6.66-6.78 (m, 1H), 7.15-7.33 (m, 5H).

(3,4-Dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonate hydrochloride[XIVc] was obtained from [XIVa] by the standard procedure. ¹H NMR(CDCl₃) δ1.43-2.22 (m, 7H), 2.42-2.70 (m, 2H), 3.13 (s, 2H), 3.28-3.50(m, 2H), 3.67 (s, 6H), 3.79 (s, 3H), 3.82 (s, 3H), 4.07 (br. s, 2H),6.45-6.65 (m, 2H), 6.70-6.80 (m, 1H), 7.37-7.52 (m, 3H), 7.52-7.73 (m,2H), 12.32 (m, 1H)

1.4 Preparation of(3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonic acidp-toluenesulfonate [XVa]

A mixture of dimethyl (3,4-dimethoxybenzyl) (N-benzyl-4-piperidylmethyl)malonate [XIVa] (36.0 g), 85% potassium hydroxide (25.3 g),methanol (40 mL) and water (30 mL) was refluxed under stirring for 20hours. The mixture was evaporated under vacuum and water solution ofresidue was added dropwise to, the stirred at 0-5° C. solution ofp-toluenesulfonic acid monohydrate (100.0 g) in 100 mL of water. Theprecipitated solid was filtered off, washed with cold water and dried togive (3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonic acidp-toluenesulfonate [XVa].

1.5 Preparation of donepezil [VII]

Phosphorous pentoxide (1.0 g) was dissolved in methanesulfonic acid(10.0 g) at 90° C.(3,4-Dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonic acidp-toluenesulfonate [XVa] (2.0 g) were added to the solution at 55° C.The mixture was stirred vigorously for 2 hours at 55-65° C. and pouredon crushed ice. The obtained mixture was extracted with dichloromethane.The organic layer was washed with 5% aqueous sodium carbonate solution,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude donepezil was purified by columnchromatography on silica gel (dichloromethane methanol from 100:0 to96:4 v/v) to give donepezil [VII]. ¹H NMR is in agreement with theliterature.

EXAMPLE 2

Preparation of Donepezil [VII]

2.1 Preparation of diethyl (4-piperidylmethylene)malonate [XXIXb]

A solution of diethyl (4-pyridylmethylene)malonate [XXVIIIb] (97.6 g) inabsolute ethanol (1 L) was hydrogenated in the presence of acetic acidglacial (35.5 g) and 10% Palladium on activated carbon catalyst (9.7 g)at 60° C. and 200 psi for 20 hours. The catalyst was filtered off andthe resulting solution of the title compound in the form of acetic acidsalt was used directly in the next step.

2.2 Preparation of diethyl (N-benzyl-4-piperidylmethyl)malonate [XXIIb]

Benzyl chloride (54.4 g) and sodium carbonate (149.4 g) were added tothe solution of the acetic acid salt of diethyl(4-piperidylmethyl)malonate [XXIXb] from the previous step. The obtainedslurry was stirred for 12 hours at 60-65° C. and evaporated underreduced pressure. Water was added to the residue and the obtainedmixture was extracted with dichloromethane. The organic layer was washedwith water, dried over sodium sulfate, passed through short silica gelcolumn and evaporated under reduced pressure. The obtained residue waswashed with hexanes and dried under reduced pressure to give diethyl(N-benzyl-4-piperidylmethyl)malonate [XXIIb].

Diethyl (N-benzyl-4-piperidylmethyl)malonate hydrochloride [XXIIc] wasobtained from diethyl (N-benzyl-4-piperidylmethyl)malonate [XXIIb] bythe standard procedure. ¹H NMR (CDCl₃), δ1.11 (t, 6H, J=7.1 Hz),1.25-1.55 (m, 1H), 1.55-2.05 (m, 5H), 2.50-2.77 (m, 2H), 3.23 (t, 1H,J=7.8 Hz), 3.33 (br. d, 2H, J=12.5 Hz), 4.03 (q, 4H, J=7.1 Hz), 4.12 (d,2H, J=4.8 Hz), 7.28 (m, 3H), 7.53 (m, 2H), 11.67 (m, 1H).

2.3 Preparation of diethyl(3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonate [XIVb]

A solution of diethyl (N-benzyl-4-piperidylmethyl)malonate[XXIIb] (11.3g) in THF (30 mL) was added dropwise to a mixture of sodium hydride, 60%suspension in mineral oil (1.95 g) and THF (15 mL). After the evolutionof hydrogen stopped, 3,4-dimethoxybenzyl chloride [IIIb] (7.3 g) wasadded to the mixture and the resulting mixture was stirred at 20-25° C.for 12 hours. A solution of absolute ethanol (1 mL) in THF (10 mL) wascarefully added under stirring to the cold mixture until the evolutionof hydrogen has stopped. Then the reaction mixture was concentratedunder reduced pressure to about half volume and treated with a mixtureof ice and 5% aqueous citric acid followed by neutralization withaqueous sodium hydrogen carbonate solution. The product was extractedwith dichloromethane, the organic layer was washed with water, driedover sodium sulfate, passed through short silica gel column to obtaindiethyl (3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonate[XIVb], ¹H NMR (CDCl₃), δ1.19 (t, 6H, J=7.1 Hz), 1.19-1.38 (m, 2H),1.38-1.63 (m, 3H), 1.77 (d, 2H, J=4.7 Hz), 1.82=2.02 (m, 2H), 2.80 (br.d, 2H, J=11.4 Hz), 3.19 (s, 2H), 3.43 (s, 2H), 3.78 (s, 3H), 3.80 (s,3H), 4.11 (q, 4H J=7.1 Hz), 6.52-6.65 (m, 2H), 6.65-6.77 (m, 1H),7.18-7.32 (m, 5H).

Diethyl (3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonatehydrochloride [XIVd] was prepared from diethyl(3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonate [XIVb]according to the standard procedure. ¹H NMR (CDCl₃), δ1.16 (t, 6H, J=7.1Hz), 1.50-1.85 (m, 5H), 1.85-2.13 (m, 2H), 2.35-2.70 (m, 3H), 3.10 (s,2H), 3.25-3.45 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.97-4.20 (m, 6H),6.44-6.60 (m, 2H), 6.67 (d, 1H, J=7.9 Hz), 7.28-7.42 (m, 3H), 7.50-7.64(m, 2H), 12.13 (m,1H)

2.4 Preparation of(3,4-dimethoxybenzyl)(N-benzyl-4-piperidyl-methyl)malonic acid [XV]

A mixture of diethyl(3,4-dimethoxybenzyl)(-benzyl-4-piperidylmethyl)malonate [XIVb] (36.0g), 85% potassium hydroxide (23.9 g), 96% ethanol (40 mL) and water (30mL) was refluxed for 20 hours. After evaporation of ethanol, theresidual aqueous solution was acidified with 32% hydrochloric acid to pH4 at 0-5° C. The precipitated solid was filtered off, washed with waterand dried to give(3,4-dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonic acid [XV], NMR¹H (DMSO-d₆) δ0.81-1.09 (m, 2H), 1.25 (br. s, 2H), 1.25-1.48 (m, 3H),1.74-1.93 (br. t, 2H), 2.60 (br. d, 2H, J=10.7 Hz), 2.89 (s, 2H), 3.28(s, 2H), 3.59 (s, 6H), 6.56 (br. d, 1H, J=8.0 Hz), 6.64 (br. s, 1H),6.69 (d, 1H, J=8.0 Hz), 7.15 (m, 5H); NMR ¹H (NaOD-D₂O) δ1.10-1.95 (m,7H), 2.42-3.68 (m, 8H), 3.68 (s, 6H), 4.18 (s, 2H), 6.60-6.90 (m, 4H),7.43 (m, 3H), 7.59 (m, 2H), 10.78 (m, 1H).

2.5 Preparation of donepezil [VII]

Phosphorous pentoxide (1.0 g) was added to methanesulfonic acid (10.0 g,104 mmol) and the mixture was stirred at 90° C. to complete dissolutionof phosphorous pentoxide. The mixture was cooled to 55° C. and(3,4-dimethoxybenzyl)(N-benzyl4-piperidylmethyl)malonic acid [XV] (2.0g) was added over a period of 10 min. The obtained mixture was stirredvigorously for 2 hours at 55-65° C. The reaction mixture was poured intocrushed ice and extracted with dichloromethane. The organic layer waswashed with aqueous sodium carbonate, dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude donepezilwas purified by column chromatography on silica gel(dichloromethane:methanol from 100:0 to 96:4) to give donepezil [VII]NMR ¹H (CDCl₃) is in agreement with the literature.

EXAMPLE 3

Preparation of Donepezil

3.0 Preparation of triethyl phosphonoacetate

A 10 L glass reactor equipped with a mechanical stirrer, a digitalthermometer, a heating mantle and a reflux condenser, connected to adistillation head was charged with triethyl phosphite (3.69 Kg, 22.2mol) and ethyl chloroacetate (2.72 Kg, 22.2 mol). The reactor was filledwith argon and the reaction mixture was heated to 120° C. The stirringwas continued for 3 hours and the temperature of the solution was raisesto 165° C., during this time some triethyl phosphite and ethylchloroacetate was distilled off. Then, the reaction mixture was heatedto 174° C. and the solution was left overnight. The reaction mixture wasfractionationally distilled under reduced pressure (10-11 mbar) to give4.43 Kg (89.3% yield) triethyl phosphoacetate with 98.2% purity by GC.

3.1 Preparation of triethyl 3,4-dimethoxy-α-phosphonocinnamate [XXX]

A 100 L glass reactor equipped with a mechanical stirrer, a droppingfunnel, a thermometer and a bubbler was charged with veratraldehyde(3.45 Kg, 20.8 mol), triethyl phosphonoacetate (4.65 Kg, 20.7 mol) anddichloromethane (53.5 Kg) and filled with argon. The solution oftitanium (IV) chloride (7.87 Kg, 41.5 mol) in dichloromethane (16.2 Kg)was added dropwise to the stirred mixture while keeping the temperaturebetween −5° and 0° C. The mixture was stirred for an additional 2 hoursat the same temperature. Triethylamine (8.40 Kg, 83.0 mol) was addeddropwise to the stirred mixture for three hours while keeping thetemperature between −5 and 0° C. The obtained mixture was stirred for anadditional 0.5 hour at the same temperature. The reaction mixture waspoured under stirring into water at 20÷25° C. The organic layer wasseparated and aqueous layer was extracted with dichloromethane. Thecombined organic extracts were consequently washed with water, sodiumhydrogencarbonate aqueous solution and again with water. The organiclayer was dried over sodium sulfate, passed through silica gel columnand the solvent was removed under reduced pressure to afford 7.45 Kg(96.6% yield) of triethyl 3,4-dimethoxy-α-phosphonocinnamate [XXX] asyellow oil.

¹H NMR (CDCl₃) δ1.20-1.39 (m, 9H), 3.79 (s, 3H), 3.84 (s, 3H), 4.11 (p,4H, J=7.4 Hz), 4.24 (q, 2H, J=7.2 Hz), 6.80 (d, 1H, J=8.3 Hz), 6.97 (d,1H), 7.00 (dd, 1H, J=8.3 Hz), 7.49 (d, 1H, J=24.4 Hz).

This material was used in the next stage without further purification.

3.2 Preparation of triethyl (3,4dimethoxybenzyl)phosphonoacetate [XIIIa]

A 100 L glass reactor equipped with a mechanical stirrer, a thermometer,a dropping funnel and a bubbler was charged with triethyl3,4-dimethoxy-α-phosphonocinnamate [XXX] (6.86 Kg, 18.4 mol) and abs.ethanol (26.0 Kg) and filled with argon. A solution of sodiumborohydride (261.0 g, 6.90 mol) in abs. ethanol (7.0 Kg) was addeddropwise to the mixture under stirring for 3 hours while keeping thetemperature of the mixture at 0-5° C. The obtained mixture was stirredfor 3.5 h at 15-20° C. Glacial acetic acid (770.0 g, 12.8 mol) was addeddropwise to the mixture at 15-20° C. The reaction mixture was stirred0.5 h at the same temperature and the solvent was removed under reducedpressure. The residue was dissolved in a mixture of dichloromethane (15Kg) and water (13 Kg). An organic layer was separated and the aqueouslayer was extracted with dichloromethane. The combined organic layerswere washed with water, dried over sodium sulfate, passed through ashort silica gel column and solvent was removed under reduced pressureto afford 6.72 Kg (97% yield) of triethyl(3,4-dimethoxybenzyl)phosphonoacetate [XXIIIa] 98% purity by GC asyellow oil which was not further purified.

¹NMR (CDCl₃) d 1.04 (t, 3H, J=7.2 Hz), 1.19-1.27 (m, 6H), 3.04-3.22 (m,3H), 3.71 (s, 3H), 3.73 (s, 3H), 3.90-4.10 (m, 6H), 6.55-6.70 (m, 3H).

3.3 Preparation of isomeric mixture of ethyl2-(3,4-dimethoxy-benzyl)-3-(4-pyridyl)acrylate [XXVa] and ethyl3,4-dimethoxy-α-(4-pyridylmethyl)cinnamate [XXVIa]

A 100 L glass reactor equipped with a mechanical stirrer, a thermometer,a dropping funnel and a bubbler was charged with triethyl(3,4-dimethoxybenzyl)phosphonoacetate [XXIIIa] (13.44 Kg, 35.4 mol) isand 4-pyridinecarboxaldehyde (5.00 Kg, 46.7 mol) and filled with argon.A solution of potassium carbonate (15.10 Kg, 109 mol) in water (15.1 Kg)was added dropwise to the mixture under stirring while keeping thetemperature of the mixture at 10-15° C. The obtained mixture was stirredovernight at 15-20° C. and kept without stirring for 3 hours at the sametemperature. Upper organic layer was separated and water was added tothe aqueous layer. The obtained aqueous solution was extracted withdichloromethane. The combined organic layers were washed with water,dried over sodium sulfate, passed through a short silica gel column andthe solvent was removed under reduced pressure to afford 10.47 Kg (89%yield) of a mixture of [XXVa] and [XXVIa] as yellow oil. The mixture wasused in the next stage without further purification.

Analytical samples of [XXVa] and [XXVIa] were separated from the mixtureby column chromatography on silica gel (hexanes-ethyl acetate from 100:0to 0:100 v/v).

[XXVa]: ¹H NMR (CDCl₃) δ1.22 (t, 3H, J=7.1 Hz), 3.75-3.85 (m, 8H), 4.18(q, 2H, J=7.1 Hz), 6.55-6.65 (m. 2H), 6.74 (d, 1H, J=8.8 Hz), 7.21 (d,2H, J=5.7 Hz), 7.71 (s, 1H), 8.56 (d, 2H, J=5.7 Hz)

[XXVIa]: ¹H NMR (CDCl₁₃) δ1.01 (t, 3H, J=7.1 Hz), 3.68 (s, 2H), 3.83 (s,6H), 4.04 (q, 2H, J=7.1 Hz), 6.44 (s, 1H), 6.70-6.80 (m, 3H), 7.12 (d,2H, J=5.8 Hz), 8.50 (d, 2H, J=5.9 Hz)

3.4 Preparation of ethyl2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionate [XXVIIa]

A 18 L stainless steel high pressure “Parr” reactor was charged with 10wt. % palladium on activated carbon (175 g), sodium acetate (262 g),glacial acetic acid (480 g), a mixture of [XXVa] and [XXVIa] (1200 g,3.67 mol), abs. ethanol (12 L) and filled consequently with nitrogen andhydrogen. The hydrogenation was carried out at hydrogen pressure of 250psi at 90° C. Then, the reactor was cooled to room temperature and thecatalyst was filtered off (the catalyst may be used repeatedly infollowing reactions). The obtained solution of [XXVIIa] was used for thenext step without further purification.

[XXVIIa]: ¹H NMR (CDCl₃) δ1.09 (t, 3H, J=7.1 Hz), 0.80-1.45 (m, 4H),1.45-1.80 (m, 3H), 2.35-2.90 (m, 5H), 2.97 (br. d, 2H, J=12.2 Hz), 3.79(s, 6H), 3.90-4.05 (m, 2H), 6.55-6.65 (m, 2H), 6.71 (d, 1H, J=8.7 Hz)

Ethyl 2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionate hydrochloride[XXVIIb] was prepared from [XXVIIa] by the standard procedure.

[XXVIIb]: ¹H NMR (CDCl₃) δ1.13 (t, 3H, J=7.2 Hz), 1.30-2.00 (m, 7H),2.55-2.90 (m, 5H), 3.41 (br. d, 2H, J=12.5 Hz), 3.83 (s, 6H1), 4.04 (q,2H, J=7.2 Hz), 6.55-6.70 (m, 2H), 6.74 (d, 1H, J=8.3 Hz), 9.05-9.25 (m,1H), 9.40-9.60 (m, 1H).

3.5 Preparation of ethyl2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionate [XVIIa].

A 20 L glass reactor, equipped with a heating mantle, a mechanicalstirrer, a thermometer, a dropping funnel and a condenser connected to abubbler was charged with the solution of [XXVIIa] from the previousstep, sodium carbonate (1.35 Kg, 12.7 mol) and benzyl chloride (743.0 g,5.87 mol) and filled with argon. The mixture was stirred at 60-65° C.for 8 h and evaporated under reduced pressure. Water (6.0 Kg) andtoluene (3.8 Kg) were added to the residue. The mixture was stirred atroom temperature until complete disappearance of solid phase. Theorganic layer was separated and the aqueous layer was extracted withtoluene. The combined organic solution was extracted with 20% aqueoussolution of citric acid (7.8 Kg). The aqueous solution was basified topH 10 with sodium carbonate and extracted with dichloromethane. Theorganic extract was dried over sodium sulfate, filtered, passed throughshort silica gel column and evaporated under reduced pressure to give1.82 Kg (80% yield from the mixture of compounds [XXVa] and [XXVIa]) ofthe compound [XVIIa] as yellow oil with 96.7% purity by GC.

¹H NMR (CDCl₃) δ1.08 (t, 3H, 7.1 Hz), 1.10-1.90 (m, 7H), 2.10-2.35 (m,2H), 2,55-3.00 (m, 3H), 3.15 (br. d, 2H, J=10.4 Hz), 3.80 (s, 8H), 3.98(q, 2H, J=7.1 Hz), 6.55-6.65 (m, 2H), 6.72 (d, 1H, J=8.6 Hz), 7.31 (s,5H).

The product was used in the next stage without further purification.

3.6 Preparation of2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionic acid [XVI]

A 100 L glass reactor equipped with a mechanical stirrer, a thermometerand a condenser connected to a bubbler was charged with ethyl2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionate [XVIIa](4.50 Kg, 10.6 mol), 90% potassium hydroxide (1.02 Kg, 16.4 mol),methanol (5.0 Kg) and water (5.0 Kg) and filled with argon. The mixturewas refluxed under stirring for 3.5 hours, cooled to room temperatureand washed with toluene (2×4.0 Kg). An aqueous layer was acidified to pH8 with 20% aqueous solution of citric acid and water (10.0 Kg) was addedto the mixture. Methanol (4.0 Kg) was evaporated from the suspension at90° C. The obtained mixture was stirred at 0° C. for about 3 hours. Theprecipitated crystalls were filtered off and washed on filter withwater. The wet crude product was dissolved in methanol (8.0 Kg). Water(22.0 Kg) was added to the vigorously stirred solution and methanol (4.0Kg) was evaporated at 90° C. The mixture was stirred for 3 hours at 0-5°C. The precipitated crystalls were filtered off, washed on filter withwater and dried at 60° C. under reduced pressure. The crystallineresidue was triturated with acetone (10 Kg), filtered off, washed onfilter with cold acetone and dried under reduced pressure at 60° C. togive 3.28 Kg (82% yield) of2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionic acid [XVI] asoff-white crystals with 99.9% purity by HPLC, mp 116-118° C. Assay bynon-aqueous titration 98.7% (on dry basis), water content (KF)—0.96%.

¹H NMR (DMSO-D₆) δ0.90-1.42 (m, 4H), 1.42-2.07 (m, 5H), 2.46-2.92 (m,5H), 3.40 (s, 2H), 3.69 (s, 3H), 3.70 (s, 3H), 6.66 (br. d, 1H, J=8.2Hz), 6.75 (br s, 1H), 6.81 (d, 1H, J=8.2 Hz), 7.18-7.42 (m, 5H).

3.7 Preparation of donepezil [VII]

A 50 L glass reactor equipped with a mechanical stirrer, a droppingfunnel, a thermometer and a condenser connected to a bubbler was chargedwith phosphorus pentoxide (1.40 Kg) and methanesulfonic acid (13.37 Kg)and filled with argon. The mixture was stirred at 70-80° C. untilcomplete homogenization. Dichloromethane (4.0 Kg) and2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionic acid [XVI](2.50 Kg, 6.29 mol) were added to the mixture at 35-40° C. The obtainedmixture was stirred under reflux for 1.5 hour. A 100 L glass reactorequipped with a mechanical stirrer was charged with crushed Ice (18.0kg) and filled with argon. The cold reaction mixture was added to theice and the mixture was stirred for 15 min. The aqueous layer of themixture was adjust to pH 8.0 by addition potassium hydroxide to thestirred mixture at 10-15° C. The organic layer was separated and theaqueous layer was extracted with dichloromethane. The combined organicextracts were dried over sodium sulfate, passed through short silica gelcolumn and evaporated under reduced pressure. The residue* (2.40 Kg,quantitative yield, one spot on TLC) was dissolved in diisopropyl ether.The obtained solution was kept overnight at room temperature and 2 hoursat 0-5° C. The precipitated crystals were filtered off, washed withdiisopropyl ether and dried under reduced pressure to give 2.21 Kg (92%yield) of donepezil [VII] as off-white crystalls with 99.9% purity byHPLC. ¹H NMR (CDCl₃) is in agreement with the literature.

* A small portion of the residue was dissolved in methylene chloride. A10% solution of hydrogen chloride in ethyl acetate was added to theresulting solution, followed by concentration under reduced pressure toobtain a crystals, which was twice recrystallized frommethanol-isopropyl ether to obtain with 85% yield donepezilhydrochloride, 100.0% purity by HPLC, mp 220-221° C.

EXAMPLE 4 Preparation of5,6-dimethoxy-2-(N-benzoyl-4-piperidylmethyl)-1-oxoindane [XXXIV]

4.1 Preparation of 2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionicacid [XXXII]

A 2 L stainless steel high pressure “Parr” reactor was charged with 10wt. % palladium on activated carbon (4.0 g), glacial acetic acid (20.8g), 2-(3 4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionic acid[XVI] (86.0 g) and methanol (1.0 L) and filled consequently withnitrogen and hydrogen. The hydrogenation was carried out at hydrogenpressure from 100 to 150 psi at 60° C. for 2.5 h. The reactor was cooledto room temperature and catalyst was filtered off. The obtained solutionwas evaporated under reduced pressure to give2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionic acid [XXXII].

1H NMR (D₂O) δ0.90-1.50 (m, 5H), 1.50-1.75 (m, 2H), 2.30-2.55 (m, 3H),2.55-2.78 (m, 2H), 3.02-3.18 (m, 2H), 3.51 (s, 3H), 3.55 (s, 3H), 6.50(br.d, 1H, J=7.8 Hz), 6.55-6.63 (m, 2H)

4.2 Preparation of2-(3,4-dimethoxybenzyl)-3-(N-benzoyl-4-piperidine)propionic acid[XXXIII]

A 2 L glass round bottom flask equipped with an ice-water bath, amagnetic stirrer, a thermometer, a dropping funnel and a bubbler wascharged with 2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionic acid[XXXII] (50 g), potassium carbonate (138.0 g), water (0.75 L) and filledwith argon. Benzoyl chloride (42.9 g) was added dropwise to the stirredmixture at 5-10° C. The obtained mixture was stirred for 3 h at roomtemperature. A 16 wt. % hydrochloric acid was added dropwise to themixture at 10-15° C. until reaching pH 3. The mixture was stirred for 1h at the same temperature. The precipitated solid was filtered off,washed with water and dried under reduced pressure to give the desired2-(3,4-dimethoxybenzyl)-3-(N-benzoyl-4-piperidine)propionic acid[XXXIII].

¹H NMR (CDCl₃) δ0.88-1.95 (m, 7H), 2.55-3.05 (m, 5H), 3.60-3.80 (m, 1H),3.82 (s, 3H), 3.83 (s, 3H), 4.55-4.78 (m, 1H), 6.65-6.70 (m, 2H), 6.75(d, 1H, J=8.7 Hz), 7.30-7.50 (m, 5H)

4.3 Preparation of5,6-dimethoxy-2-(N-benzoyl-4-piperidylmethyl)-1-oxoindane [XXXIV]

A 250 mL round bottom flask equipped with a water bath, a magneticstirrer and a condenser connected to a bubbler was charged withPhosphorus pentoxide (15.1 g) and methanesulfonic acid (145 g) andfilled with argon. The mixture was stirred at 75° C. until a completedisappearance of the solid phase and cooled to 35-40° C. Dichloromethane(50 mL) and 2-(3,4-dimethoxybenzyl)-3-(N-benzoyl-4-piperidine)propionicacid [XXXIII] (27.4 g) were added to the mixture. The obtained mixturewas refluxed under stirring for 1.5 hour. The reaction mixture wascooled to room temperature and poured into Ice. The organic layer wasseparated and water layer was extracted with dichloromethane. Thecombined organic solution was washed with sodium carbonate aqueoussolution, dried over sodium sulfate, passed through a short silica gelcolumn and evaporated to dryness. The crystalline residue (25.1 g, 96.2%yield, lone spot on TLC) was re-crystallized from the mixture ofmethanol and isopropyl ether to give 21.5 g (82.4% yield) of compound[XXXIV] as off-white crystalls.

¹H NMR (CDCl₃) δ1.07-1.48 (m,3H), 1.58-2.00 (m, 4H), 2.62-3.12 (m, 4H),3.24 (dd, 1H, J=17.5, 8.1 Hz), 3.65-3.85 (m, 1H), 3.88 (s, 3H), 3.93 (s,3H), 4.62-4.82 (m, 1H), 6.83 (s, 1H), 7.14 (s, 1H), 7.36 (s, 5H)

EXAMPLE 5 Preparation of 2-(N-benzyl-4-piperidylmethyl)-1-oxoindanehydrochloride [VIIb]

5.1 Preparation of an isomeric mixture of ethyl2-benzyl-3-(4-pyridyl)acrylate [XXVb] and ethylα-(4-pyridylmethyl)-cinnamate [XXVIb]

A 250 mL glass round bottom flask equipped with an ice-water bath, amechanical stirrer, a thermometer, a dropping funnel and a bubbler wascharged with triethyl benzylphosphonoacetate [XXIIIb] (82.6 g) and4-pyridinecarboxaldehyde (39.8 g) and filled with argon. A solution ofpotassium carbonate (109.5 g) in water (105.0 g) was added dropwise tothe mixture at 10-15° C. The obtained mixture was stirred for 22 h atroom temperature, diluted with water and extracted twice withdichloromethane. The combined organic layer was dried over sodiumsulfate, passed through short silica gel column and evaporated underreduced pressure to give 60.0 g (85.4% yield) of a mixture of [XXVb] and[XXVIb] which was used in the next step without furter purification.

[XXVb]: ¹H NMR (CDCl₃) δ1.20 (t, 3H, J=7.1 Hz), 3.86 (s, 2H), 4.17 (q,2H, J=7.1 Hz), 7.75 (s, 1H), 8.56 (d, 2H, J=5.6 Hz)

[XXVIb]: ¹H NMR (CDCl₃) δ0.97 (t, 3H, J 7.1 Hz), 3.73 (s, 2H), 4.01 (q,2H, J=7.1 Hz), 6.47 (s, 1H), 7.08 (d, 2H, J=5.7 Hz), 8.49 (d, 2H, J=5.7Hz)

5.2 Preparation of ethyl 2-benzyl-3-(4-piperidine)propionate [XXVIIc]

A 2 L stainless steel high pressure “Parr” reactor was charged with 10wt. % palladium on activated carbon (4.0 g), glacial acetic acid (26.0g), mixture of [XXVb] and [XXVIb] from previous stage (60.0 g) and abs.ethanol (1.0 L) and filled consequently with nitrogen and hydrogen. Thehydrogenation was carried out under hydrogen pressure of 250 psi at 90°C. Then, the reactor was cooled to room temperature and the catalyst wasfiltered off. The obtained solution of [XXVIIc] was used in the nextstep without further purification.

5 .3 Preparation of ethyl 2-benzyl-3-(N-benzyl-4-piperidine)propionatehydrochloride [XVIIc]

2 L round bottom flask equipped with a heating mantle, a mechanicalstirrer, a thermometer, a dropping funnel and a condenser connected to abubbler was charged with a solution of [XXVIIc] from the previous step,sodium carbonate (73.3 g) and benzyl chloride (32.7 g) and filled withargon. The mixture was stirred at 60-65° C. for 9 h and evaporated underreduced pressure. Water (300 mL) and toluene (300 mL) were added to theresidue. The mixture was stirred at room temperature until completedisappearance of solid phase. The organic layer was separated and theaqueous layer was extracted with toluene. The combined organic solutionwas dried over sodium sulfate, filtered and evaporated under reducedpressure to give 69.5 g (84.7% yield on two stages) of ethyl2-benzyl-3-(N-benzyl-4-piperidine)propionate [XVIIb] as yellow oil. ¹HNMR (CDCl₃) δ1.10 (t, 3H, J=7.1 Hz), 1.07-1.42 (m, 4H), 1.50-1.78 (m,3H), 1.78-1.97 (br. t 2H), 2.64-2.97 (m, 5H), 4.02 (q, 2H, J=7.1 Hz),7.10-7.32 (m, 10 H).

Ethyl 2-benzyl-3-(N-benzyl-4-piperidine)propionate hydrochloride [XVIIc]was obtained from [XVIIb] by the standard procedure. ¹H NMR (CDCl₃)δ1.07 (t, 3H, J=7.1 Hz), 1.27-1.59 (m, 2H), 1.59-2.22 (m, 6H), 2.40-2.98(m, 5H), 3.38 (br. d, 2H, J=11.6 Hz), 3.99 (q, 2H, J=7.1 Hz), 4.07 (d,2H, J=4.9 Hz), 7.04-7.71 (m, 10 H), 12.32 (m, 1H).

5.4 Preparation of 2-benzyl-3-(N-benzyl-4-piperidine)propionic acid[XVIIb]

A 500 mL round bottom flask equipped with a heating mantle, a mechanicalstirrer, a thermometer and a condenser connected to a bubbler wascharged with ethyl 2-benzyl-(N-benzyl-4-piperidine)propionatehydrochloride [XVIIc] (66.9 g), 90% potassium hydroxide (26.0 g),methanol (140 mL) and water (70 mL) and filled with argon. The mixturewas refluxed under stirring for 15 h, concentrated under reducedpressure to the volume of about 150 mL, acidified to pH 8 with 20%aqueous solution of citric acid and extracted with dichloromethane.Combined organic extract was dried over sodium sulfate, filtered andevaporated under reduced pressure to give 56.1 g (quantitative yield) of2-benzyl-3-(N-benzyl-4-piperidine)propionic acid [XVIa].

¹H NMR (CD₃OD) δ0.80-1.35 (m, 4H), 1.42-1.64 (m. 2H), 1.64-1.97 (m, 3H),2.38-2.59 (m, 2H), 2.67-2.94 (m, 3H), 3.37 (s, 2H), 6.97-7.26 (m, 10 H).

5.5 Preparation of 2-(N-benzyl-4-piperidylmethyl)-1-oxoindanehydrochloride [VIIb]

A 250 mL round bottom flask equipped with a mechanical stirred, adropping funnel, a thermometer and a condenser connected to a bubblerwas charged with phosphorus pentoxide (13.3 g) and methanesulfonic acid(133 g) and filled with argon. The mixture was stirred at 90-95° C.until complete homogenization. Dichloromethane (40 mL) and2-benzyl-3-(N-benzyl-4-piperidine)propionic acid [XVIa] (26.6 g) wereadded to the mixture at 35-40° C. The obtained mixture was stirred underreflux for 3 hours. Then the cold reaction mixture was poured intocrushed ice and the mixture was made basic with aqueous potassiumhydroxide to pH 9-10. The mixture was extracted with dichloromethane.The combined organic extract was dried over sodium sulfate, passedthrough short silica gel column and evaporated under reduced pressure.The residue (25.1 g, quantitative yield, one spot on TLC) was treatedwith a solution of hydrogen chloride in methanol and the resulting solidwas recrystallised from mixture of methanol-ether to give 24.3 g (86.5%yield) of compound [VIIb], mp 199-200° C.

¹H NMR (CDCl₃) δ1.40-2.23 (m, 8H), 2.53-2.83 (m, 4H), 3.23-3.57 (m, 3H),4.12 (d, 2H, J=4.9 Hz), 7.26-7.72 (m, 9H), 12.26 (m, 1H)

What is claimed is:
 1. A process for the preparation of a compound offormula [Ib] including optical isomers and salts

wherein: R⁴, R⁵, R⁶ and R⁷ are identical or different and eachrepresents hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, or halogen; R¹⁰ isselected from benzyl, C₁₋₆ alkyl, ω-aralkyl, acyl and C₁₋₆alkoxycarbonyl, which process comprises the following steps: a) reactinga compound of the following formula

 wherein R⁸ and R⁹ are identical or different and each represents C₁₋₆alkyl and R⁴, R⁵, R⁶ and R⁷ are as defined above with4-pyridinecarboxaldehyde in the presence of base to give a compound ofthe formula

wherein the dotted lines represent two possible locations of the doublebond formed in the reaction, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above,including tautomers, stereoisomers or mixtures thereof as well as acidaddition salt thereof; b) catalytic hydrogenation of the compound ormixture of compounds or their salts obtained in step (a) to give acompound of the following formula

wherein R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above, as well as acidaddition salt thereof; c) reacting the compound obtained in step b)above or a salt thereof with a compound of formula R¹⁰X, wherein R¹⁰ isas defined above and X is a leaving group, to yield a compound of thefollowing formula

wherein R⁴, R⁵, R⁶, R⁷, R⁸ and R¹⁰ are as defined above, or its salt;following hydrolysis of the ester group to form the correspondingcarboxylic acid or a salt thereof; d) intramolecular cyclization of thecarboxylic acid obtained in step c) above or salts thereof to yield thecompound [Ib]; e) optionally converting the resulting compound offormula [Ib] into a pharmacologically acceptable salt.
 2. Processaccording to claim 1 wherein R⁴ and R⁷ are hydrogen, R⁵ and R⁶ are eachmethoxy.
 3. Process according to claim 1, wherein said compound offormula [Ib] is donepezil.
 4. A compound of the formula

wherein R⁴, R⁵, R⁶ and R⁷ are as defined in claim 1, R¹¹ is hydrogen oris selected from benzyl, C₁₋₆ alkyl, ω-aralkyl, acyl and C₁₋₆alkoxycarbonyl, R¹² is hydrogen or C₁₋₆ alkyl, including optical isomersand salts thereof.
 5. A compound of the formula

wherein the dotted lines represent two possible locations of the doublebond, R⁴, R⁵, R⁶ and R⁷ are identical or different and each representshydrogen, C₁₋₆ alkyl, or halogen; and R⁸ is C₁₋₆ alkyl, includingtautomers, stereoisomers or mixtures thereof as well as acid additionsalt thereof, with the proviso that when three of R⁴-R⁷ are H, the otherone is halogen or C₁₋₆ alkoxy.